Kaposi's sarcoma is the most frequent tumor arising in HIV-infected patients. Despite extensive investigation, Kaposi's sarcoma remains an incurable disease. Novel approaches for its treatment, particularly systemic Kaposi's sarcoma, are required. I am proposing an innovative approach, utilizing tumor lethal factor (LeTx) to block Kaposi's sarcoma viral G-protein coupled receptor (vGPCR) signaling. Several years ago I established that LeTx proteolytically inactivates mitogen activated protein kinase kinases (MAPKKs or MEKs). This is significant since MEK signaling is known to be required for expression of factors which promote tumor cell proliferation and vascularization of Kaposi's sarcoma. Moreover, my colleagues and I have demonstrated that LeTx can potently inhibit fibrosarcoma growth and vascularization and induce apoptosis of human melanoma in the absence of any apparent toxicity. Consequently, I hypothesize that tumor lethal factor will be an effective therapeutic for Kaposi's sarcoma. The objective of this proposal is to determine in principle whether growth and vascularization of Kaposi's sarcoma may be inhibited by LeTx. This will be accomplished through complementary in vitro and in vivo analyses of an immortalized endothelial cell line which expresses the Kaposi's sarcoma vGPCR as well as a human Kaposi's sarcoma-derived cell line, both of which are capable of forming angioproliferative tumors in mice which closely resemble human Kaposi's sarcoma. This approach can form the basis for the development of a Kaposi's sarcoma therapeutic for clinical applications.